Complexes containing S(+)-phenyl alkanoic acids and α-hydroxyalkanoic

ABSTRACT

Complexes containing S(+)-ibuprofen, method for the production of these complexes and pharmaceutical preparations containing these complexes are described.

The present invention relates to hydrogen-bridge-bound complexes havinga stoichiometry of 1:1 of S(+)-phenyl alkanoic acids.

Compounds of S(+)-phenyl alkanoic acids and α-hydroxyalkanoic acids arealready known. They are, however, not the specific complexes accordingto the invention but salts. As prior art in this respect attention isdrawn to EP 0 424 028 A2, DE 39 22 441 A1, DE 25 08 895 C2, DE-AS 24 19317, CH-PS 624 086, DE 38 14 887 C1 and DE38 36 863 A1.

Specification as laid open to inspection DE 38 36 863 A1 (1990)describes γ-butyrolactone which can readily dissolve water-insolublenon-steroidal antirheumatic agents, including (R, S)-ibuprofen. Assolutions, preparations which are miscible with water and other liquidsand can also be deleted as desired are named. The γ-butyrolactone isopened in the organism into the 4-hyroxybutyric acid and metabolized toCO₂ and water. In example 1, a pharmaceutical formulation in the form ofa cream, ointment or gel is disclosed and contains inter alia 1 mllactic acid. The addition of R, S or D, L-lactic acid is specified in anon-stoichiometric ratio (molar basis) in the (R, S)-ibuprofenformulation.

One problem underlying the present invention is the preparation of newsubstances on the basis. of S(+)-phenyl alkanoic acids andα-hydroxyalkanoic acids and developing their advantageous use inpharmaceutical preparations.

This problem is solved according to the invention byhydrogen-bridge-bound complexes having a stoichiometry of 1:1 comprisingS(+)-phenyl alkanoic acids and α-hydroxyalkanoic acids in which thecomplex bond is based on carboxylatecarboxyl interactions with a protonswitch of the form R₁ --COOH . . . ⁻ OOC--R₂ ⃡R₁ --COO⁻. . . HOOC--R₂where R₁ --COOH denotes the S(+)-phenylalkanoic acids and R₂ --COOH theα-hydroxyalkanoic acids and the pKa values relating, to the carboxylgroup of the S(+)-phenyl alkanoic acids lie in the range of 3.5-3.9 andthe pKa values relating to the carboxyl group of the in theα-hydroxyalkanoic acids lie in the range of 1.8-2.9.

Preferably, the α-hydroxyalkanoic acids have the following generalformula: ##STR1## where X = OH

Z = H. OH, NH₂

A = a bond or an alkylene chain which contains 1-10 carbon atoms and ifrequired an amino group of 1-6 hydroxyl groups.

Preferably the pKa values relating to the carboxyl group of theα-hydroxyalkanoic acids lie in the range of 1.9-2.5.

Preferably, the complexes contain the enantiomers of lactic acid.

Preferably, as S(+)-phenyl alkanoic acids herein S(+)-ibuprofen orS(+)-naproxen shall be understood and are used. Preferably asS(+)-phenyl alkanoic acids herein the substances as detailed below shallbe understood and are used. These substances comprise the followingstructure: ##STR2## in which R is lower alkyl, Ar is preferably amonocyclic, polycyclic or ortho-condensed polycyclic aromatic grouphaving up to twelve carbons in the aromatic system, e.g. phenyl,diphenyl, and naphthyl. The substituents of these aromatic groupscomprise one or more halogen atoms, C₁ -C₄ alkyls, benzyl, hydroxy, C₁-C₂ alkoxy, phenoxy and benzoyl groups. Examples of such substitutedaryls are: 4-isobutyl-phenyl, 3-phenoxy-phenyl, 2-fluoro-4-diphenyl,4'-fluoro-4-diphenyl, 6-methoxy-2-naphthyl,5-chloro-6-methoxy-2-naphthyl and 5-bromo-6-methoxy-naphthyl,4-chloro-phenyl, 4-difluoro-methoxyphenyl, 6-hydroxy-2-naphthyl, and5-bromo-6-hydroxy-2-naphthyl.

Preferably, the complexes consist of S(+)-phenyl alkanoic acids,preferably of S(+)-ibuprofen and α-hydroxyalkanoic acids.

According to the invention, the complexes of the invention are preparedby the following method steps:

a) for the preparation from aqueous medium (only water) or weaklybuffered aqueous solutions covering a pH range between pH 5.5-7.5 (20°C.) a buffered aqueous solution, for example a 0.01M-0.001M-K₂ PO₄ /KH₂PO₄ buffer pH 6.0-7.5 (20° C.) is prepared and into it an equivalentamount S(+)-phenyl alkanoic acid is introduced with constant stirring;

b) the solution is heated with constant stirring to 40° C. (water bath)until a clear transparent solution is obtained (normally after 20minutes) and all the S(+)-phenyl alkane acid has gone into solution;

c) thereafter the pH of the solution is adjusted to pH 5.5-6.0 byaddition of diluted phosphoric acid (H₂ PO₄) (20° C.) and then theequivalent (corresponding) amount of the α-hydroxyalkanoic acid isintroduced with constant stirring;

d) the complex formation is terminated after 20 minutes, whereupon aftercooling to 0°-4° C. the complexes precipitate in crystalline form andcan be separated from the mother liquor via a sintered glass funnel orglass filter (1G4);

e) alternatively to method step d) the clear solution can be reduced ina rotary evaporator (water bath temperature 25°-30° C.) in the water jetvacuum to half the volume, whereupon a colourless (amorphous) depositforms which is filtered off via a 1G4 glass filter and can berecrystallized from water/ethanol (70/30 V/V) or from ethyl acetate(100%).

The substances according to the invention are not a salt formationbetween an acidic group (carboxyl group of the ibuprofen) and a basicradical of the α-hydroxyalkanoic acid, but, as X-ray structure analysisand FT-IR spectra show, involve carboxylate-carboxyl interactions, thetwo carboxyl radicals of the α-hydroxyalkanoic acid and for example ofthe ibuprofen sharing a proton. This means that the complex is formed inaccordance with the X-ray structure analysis by a hydrogen bridgewithout any participation of a basic group being observed.

The complexes according to the invention may be used advantageously inpharmaceutical preparations containing one or more complexes andpossibly optionally additionally physiologically compatible usualextenders or carriers.

Particularly advantageous is a pharmaceutical preparation on the basisof phenyl alkanoic acids with anti-inflammatory, antipyretic,antimicrobial and analgesic effect, containing an active substancecomplex of a phenyl alkanoic acid and an α-hydroxyalkanoic acid andpossibly additionally usual physiologically compatible auxiliarysubstances, in which the active substance complex consists ofS(+)-phenyl alkanoic acids and α-hydroxyalkanoic acids.

Particularly advantageous is a pharmaceutical preparation on the basisof ibuprofen or naproxen with anti-inflammatory, antipyretic,antimicrobial and analgesic effect, containing an active substancecomplex of an ibuprofen or naproxen and α-hydroxyalkanoic acids andpossibly additionally usual physiologically compatible auxiliarysubstances, in which the active substance complex consists ofS(+)-ibuprofen or S(+)-naproxen and a α-hydroxyalkanoic acid andrepresents an amount by weight of 0.1-90% (w/w) of the composition.

Particularly advantageous is a pharmaceutical composition which contains50 to 800 mg, preferably 100 to 600, in particular 100 to 300 mgS(+)-ibuprofen or S(+)-naproxen.

Particularly advantageous is a pharmaceutical preparation in which thesuitable dose for oral and parenteral administration is in the range of50 to 1200 mg daily, normally between 100 and 800 mg daily, preferablybetween 200 and 600 mg S(+)-ibuprofen daily and that the suitable dosesfor a topical administration of the complex lies in the range of 10-200mg daily.

Hereinafter the "pharmaceutically active compound" in the broader senseis denoted as a complex. In medical use said pharmaceutically activecompound may be administered orally, rectally, parenterally ortopically, in particular however orally or topically. Thus, thetherapeutical composition of the present invention may be anypharmaceutical preparation known per se for oral, rectal, parenteral ortopical administrations. Pharmaceutically usual carriers which can beused in such pharmaceutical compositions are frequently described inpharmacy. The composition of this invention may correspond to 0.1-90%(w/w) of the active compound. The compositions represent normal unitarydosage forms. These dosage forms contain 50-800 mg, preferably 100-600mg or 100-300 mg, S(+)-ibuprofen.

Oral administration forms according to this invention are preferred,such as tablets, capsules, syrup and aqueous or oily suspensions.Tablets may for example be prepared by mixing the active compound withinert extenders such as for example calcium phosphate in the presence ofa disintegrating agent, for example starch, or lubricant, for examplemagnesium stearate, with subsequent conversion to tablet form in thenormal production sense. The tablets may be prepared in the form of aretard formulation of the active compound by known methods. If desired,such tablets may be prepared by correspondingly known methods so thatthey do not disintegrate in the stomach, for example with the aid ofcellulose, acetate, phthalate. Correspondingly, capsules may be made,for example soft or hard gelatin capsules, which contain thepharmaceutically active compound alone or in the presence of addedauxiliary agents. These capsules may be made by conventionalpharmaceutical technology, with or without stomachresistant coating.Other compositions for oral administration include aqueous solutionscontaining the active pharmaceutical compound in the presence of anontoxic suspension agent, for example carboxymethyl cellulose and oilysuspensions which contain the active pharmaceutical compound in thepresence of a vegetable oil.

In accordance with this invention pharmaceutical formulations may beemployed for topical administration of the active pharmaceuticalcompound. The pharmaceutically active compound in this case is dispersedin a pharmaceutically suitable cream, ointment or gel. A suitable creamcan for example be prepared in that the active pharmaceutical compoundis dispersed in a topical carrier, for example readily volatile paraffinin an aqueous medium with the aid of surfactants (detergents). Anointment can for example be prepared by mixing the pharmaceuticallyactive compound with a topical carrier, for example mineral oil orparaffin or beeswax. A gel-like formulation can be prepared by mixing anactive pharmaceutical compound with a topical carrier, for exampleCarbomer BP, in the presence of water. Topically administratablecompositions may consist inter alia of a matrix which is able todisperse the active pharmaceutical compound in such a manner that thelatter is administered transdermally by its close contact with the skin.A suitable transdermal composition may be prepared inter alia by mixingthe pharmaceutically active compound with a topical carrier, asdescribed above, together with a possible transdermal accelerator, forexample dimethyl sulfoxide or propylene glycol.

Pharmaceutical formulations in accordance with this invention which aresuitable for rectal administration are inter alia suppositories on thebasis of polyethylene glycol or cocoa butter.

Pharmaceutical formulations for parenteral administration contain knownpharmaceutical formulations, for example sterile suspensions or sterilesolutions in a suitable solvent.

In some specific pharmaceutical formulations it appears expedient tohave the pharmaceutical active compounds in the size of small particles,for example colloidal solutions or particulate suspensions of the orderof magnitude of 0.1-1 μm (colloid mill).

If desired, in accordance with this invention compositions may also beprepared with other compatible pharmaceutical active substances.

These complexes according to the invention have anti-inflammatory,antipyretic and interesting antimicrobial properties as well asanalgesic effects. These complexes have inter alia the advantage thatafter oral administration after a relatively short time they result in asubstantially higher plasma level of S(+)-ibuprofen than S(+)-ibuprofenin the form of the free acid. These complexes are therefore particularlyimportant in practice for treating acute pain; rapid onset withimmediate freedom from pain can be achieved. The treatment ofinflammations and pain is particularly important in rheumatic patientsexhibiting indications such as primary chronic polyarthritis,arthridites of rheumatic origin, articular rheumatism and musclerheumatism with their corresponding degrees of severity. These newcomplexes are particularly valuable for relieving pain, for exampleheadache, dysmenorrhea, postoperative pain, postpartum pain and painrelated to influenza and colds.

Accordingly, the invention describes in particular another aspect fortreating pain or inflammatory fever after administering atherapeutically effective dose of said complex. Although the exact doseof the pharmaceutically active compound depends on a number ofparameters, for example age of the patient, state of the patient, casehistory and compliance, a suitable dose both for oral and parenteraladministrations of S(-)-ibuprofen complex is in the range of 50-1200 mgdaily, normally between 100 and 800 mg daily, preferably between 200 and600 mg S(+)-ibuprofen ibuprofen daily administered at one time or atseveral times.

With topical administration of this complex the corresponding dose liesin the range of 10-200 mg daily, generally being 20-100 mg daily, asordered by the physician.

Advantageously, according to the invention the complexes of theinvention may also be used in pharmaceutical preparations as aredescribed in German application DE 40 15 794.6. Such isotropic solutionscan be prepared by the following method steps:

a) heating of the carrier whilst stirring to above the melting pointuntil an isotropic transparent liquid is present;

b) measuring the electrical conductivity and the viscosity at thetemperature of the melting point to ensure the presence of an isotropictransparent liquid;

c) determination of the refractive index;

d) setting the desired concentration of the pharmaceutical activesubstances whilst observing the molar fraction, which at 37° C. must liebetween 0.001 and 0.67;

e) introduction of the pharmaceutical active substance into the solventwith constant stirring;

f) stirring the mixture until the pharmaceutical active substance isdissolved and a transparent solution obtained;

g) measuring the differential refractive index increment[(Δn/Δc)_(T/P=constant) ] for determining the monomolecular solutionand/or

h) checking the native conformation and the monomolecularity of thepharmaceutical active substance in the solution by measuring the molarextinction coefficient in the UV range and taking the absorptionspectrum and detection of the chiral configuration by measuring in thepolarimeter and/or

i) measuring the opacification to ensure a homogeneous solution and/or

k) measuring the specific conductivity [(Ω)_(T),V=constant ] forcontrolling the ional concentration in the isotropic solution;

l) cooling the clear solution and preparing a galenic formulation;

m) further cooling of the solution to room temperature until thesolution has solidified.

The invention will be explained in further detail hereinafter withreference to the example of the reactant lactic acid:

(R, S)-lactic acid is a liquid at room temperature (Fp: 16.8° C.) whilstthe enantiomeric forms, D(-) and L(+)-lactic acid, are solid substances(Fp: 53°-54° C.). The enantiomers of lactic acid are slightly soluble inwater, ethanol and ether and are not hydroscopic like D, L-lactic acidIt has now been found that both D(-) and L(+)-lactic acid form withS(+)-ibuprofen a 1:1 molecular complex both in the solid state and inthe liquid state (aqueous solution). The complex is formed by preparingan aqueous solution of D(-) or L(+)-lactic acid and heating it at 35° C.together with the corresponding stoichiometric amount, molar ratio 1:1D(-) or L(+)-lactic acid and S(+)-ibuprofen, stirring and cooling againto 20° C. On further cooling to 0°-4° C. flake-like crystals appearwhich after filtration and drying at 20° C. under vacuum in a dryingpistol have a melting point of 63°-65° C. The optimum rotation of thesepreparations is as follows:

[α]₅₅₀ ²⁰ + 27° C. (=1.5, CHCl₃), for L(+)-lactic acid × S(+)-ibuprofencomplex;

[α]₅₅₀ ²⁰ + 2,5° C. (=2.5 in H₂ O), for D(-)-lactic acid ×S(+)-ibuprofen.

On recrystallization of the L(+)-lactic acid S(+)-ibuprofen complex fromanhydrous ethanol other (polymorphous) crystalline forms result whichaccording to powder patterns (Guinier method) also exhibit celldimensions different to the crystals which can be obtained from aqueousor 50% (v/v) aqueous-ethanolic solutions. The latter crystalline forms(from aqueous-ethanolic solution) have a melting point of 58°-60° C. andin accordance with gravimetric and DSC measurements contain one moleculewater as hydrate which is incorporated into the crystal lattice. Otherpolymorphous forms were obtained when crystallized from methanol/ethylacetate 50% (v/v).

According to X-ray structure analytical investigations, in this case aswell a hydrogen-bridge-bound complex is present between the carboxylgroup of the S(-)-ibuprofen and the enantiomeric form of the lacticacid, in this case as well the carboxyl group. According to particularsin the literature and own conductimetric measurements the pKa of thelactic acid is 3.55-3.88 and that of the hydroxyl is pKa = 9.5, thelactic acid not being stable at this pH. This means that under the givenproduction conditions and taking account of the pKa values of theS(+)-ibuprofen and the lactic acid, as with the α-amino acids as well,once again carboxyl-carboxylate hydrogen bridge bonds are involved whichform this complex. However, further NMR and crystal-chemicalinvestigations have shown that in addition, depending on thecrystallization conditions, further hydrogen bridge bonds occur betweenall the hydroxyls of the lactic acid and the carboxyl groups of theS(+)-ibuprofen. In both cases, once again there is no salt-like or ionpair bond between S(+)-ibuprofen and the enantiomers of lactic acid.Crystalline compounds between S(+)-ibuprofen and the racemate of thelactic acid (D, L) were likewise obtained with stoichiometric reactionin alcoholic solution. These compounds consisting of S(+)-ibuprofen and(D, L)-lactic acid have a melting point of 28° C.; [α]₅₅₀ ²⁰ = +51°(95%, EtoH), and exhibit the same structural principles as explained atthe beginning for the pure enantiomers of the lactic acid.

The pharmacokinetic and pharmacodynamic behaviour, illustrated withreference to the example of the S(+)-ibuprofen × L(+)-lactic acidcomplex, follows that of complexes consisting of S(+)-ibuprofen andα-amino acids or amino sugars: Rapid effect onset with a t_(max) of 20minutes, a high AUC of 50 mg/ml x h compared with the free acid of only40 mg/ml × h with a t_(max) of 2 h, with the same active substanceamount of 150 mg S(+)-ibuprofen. From these pharmacokinetic results itis apparent that the pharmaceutical preparation disclosed here issuperior to the free acid of S(+)-ibuprofen.

EXAMPLES 1. Preparation of S(+)-ibuprofen-L-(+)-lactic acid complex

100 g L(+)-lactic acid are dissolved in 250 ml water whilst stirring at20° C. (1.11 mol.) Under constant stirring 226.8 g (1.1 mol)S(+)-ibuprofen are introduced, the solution gradually being heated(within 10 minutes) to 35°-40 ° C. The pH of the solution should notexceed 6.0 when using a 0.001M NaHPO₄ /NaH₂ PO₄ buffer. With a simpleaqueous solution (pH 5.5-6.0) it should be ensured that the pH does notdrop below 4.0, this possibly making necessary a titration back to theoriginal pH 5.5-6.0 again with diluted NaOH. The temperature of 35°-40°C. should be strictly observed to ensure that no segregation occurs.After about 30 minutes a clear solution is obtained which is cooled to0°-4° C., whereupon the crystals of the complex form.

Alternatively, the clear solution can be cooled to 20° C. andconcentrated to about 120 ml, whereupon a fine white deposit (amorphous)forms which can be filtered off via a 1G4 glass filter.

The material thus prepared is dried overnight under vacuum in a dryingpistol at 20°-25° C. Yield: 85-90% of the theoretical value.Recrystallizing can be carried out from 50% (v/v) aqueous-ethanolicsolution or ethanol/ethyl acetate (50/50 v/v). The material,recrystallized from pure organic solvent, or the dry powder has an Fp:63°-65° C., [α]₅₅₀ ²⁰ + 27° C. (=1.5, CHCl₃); crystals fromaqueous-ethanolic solution (50% v/v) have an Fp: 58°-60° C.(decomposition) and [α]₅₅₀ ²⁰ + 21° C. (c 1.5, CHCl₃).

2. Preparation of S(+)-ibuprofen-D-(-)-lactic acid complex

The procedure of example 1 is adopted. Melting point of the complexobtained from water or ethanol-ethyl acetate (50% v/v): Fp: 63° C.;

[α]₅₅₀ ²⁰ + 2.5° C. (=2.5 in H₂ O).

3. Preparation of S(+)-ibuprofen D, L-lactic acid complex

50 g (D, L)-lactic acid (0.55 mol) are dissolved in water (200 ml)whilst stirring at room temperature. Under constant stirring, 113.4 gS(+)-ibuprofen are added, the solution being brought to 30° C. within 10minutes. After approximately half an hour complete dissolving occurs sothat the reaction mixture can be cooled to 20° C. and prepared inaccordance with the example. Yield: 90% of the theoretical value. Fp =28° C.; [α]₅₅₀ ²⁰ + 51° C. (95%, ethanol).

EXAMPLE 4

A pharmaceutical formulation can consist inter alia of

    ______________________________________                                        S(+)-ibuprofen, L(+)-lactic acid                                                                         215.5 mg                                           magnesium stearate, powder NF                                                                            5.0 mg                                             poridoul USP               20.0 mg                                            hydroxypropyl methyl cellulose USP 6 CPS                                                                 4.0 mg                                             titanium dioxide USP       1.5 mg                                             Tah USP, purified          0.5 mg                                             hydroxypropyl cellulose LF, NFL 0.3% SiO.sub.2                                                           4.0 mg                                             ______________________________________                                    

EXAMPLE 5

    ______________________________________                                        S(+)-ibuprofen, L(+)-lactic acid                                                                          307.0 mg                                          magnesium stearate, powder NF                                                                             10.0 mg                                           hydroxypropyl methyl cellulose USP 6 CPS                                                                  5.0 mg                                            Tah, USP                    1.0 mg                                            hydroxypropyl methyl cellulose LF, NFL 0.3%                                                               5.0 mg                                            Providone USP               10.0 mg                                           titanium dioxide            2.0 mg                                            ______________________________________                                    

EXAMPLE 6

A pharmaceutical formulation for injection purposes can consist interalia of:

    ______________________________________                                        S(+)-ibuprofen, L(+)-lactic acid complex                                                                28.7   mg                                           Corresponding to 20.0 mg S(+)-ibuprofen                                       Mannite                   20.0   mg                                           Water for injection purposes made up to                                                                 1.0    ml                                           ______________________________________                                    

EXAMPLE 7

The complexes consisting of S(+)-ibuprofen and L(+) or D(-)-lactic acidin the molar ratio 1:1 can also be prepared from salts of theenantiomers of the lactic acid.

In accordance with the following teaching, these complexes can beobtained almost quantitatively and with high optimum purity.

100 g L(-)-lithium lactate (1.04 mol) are dissolved whilst stirring at20° C. in a mixture of 100 ml ethanol (96% p.a.) and 100 ml water(deionized). Under constant stirring, 214.5 g (1.04 mol) S(+)-ibuprofenare slowly added, ensuring that the pH value of the reaction mixturedoes not rise above pH 5.5, making the addition of 0.01N HCl necessary.The solution is heated to 30° C. for one hour, thereafter mixed withethyl acetate (150 ml), the lithium salt precipitating and the complexbeing in the ester phase, and thereafter concentrated. The furtherprocedure follows example 1.

I claim:
 1. A hydrogen-bridge-bound complex having a stoichiometry or1:1 comprising an S(+)-phenyl alkanoic acid and an α-hydroxyalkanoicacid in which the complex bond is based on a carboxylate-carboxylinteraction with a proton switch of the form R₁ --COOH . . . ³¹ OOC--R₂⃡ R₁ --COO⁻. . . HOOC--R₂ where R₁ --COOH denotes the S(+)-phenylalkanoic acid and R₂ --COOH the α-hydroxyalkanoic acid and the pKa valuerelating to the carboxyl group of the S(+)-phenyl alkanoic acid lies inthe range of 3.5-3.9 and the pKa value relating to the carboxyl group ofthe α-hydroxyalkanoic acid lies in the range of 1.8-2.9.
 2. A complexaccording to claim 1, in which said α-hydroxyalkanoic acid has thefollowing general formula: ##STR3## where X = OHZ = H, OH, NH₂ A = abond or a member selected from the group consisting of an alkylene chainwhich contains 1-10 carbon atoms and alkylene chains substituted with amember selected from the group consisting of an amino group and 1-6hydroxyl groups.
 3. A complex according to claims 1 or 2, in which thepKa value relating to the carboxyl group of the α-hydroxyalkanoic acidlies in the range of 1.9-2.5.
 4. A complex according to claims 1 or 2,in which said α-hydroxyalkanoic acid is an enantiomer of lactic acid. 5.A complex according to claim 1 or 2, in which said S(+)-phenyl alkanoicacid is a member selected from the group consisting of S(+)-ibuprofen orS(+)-naproxen are used.
 6. A complex according to claims 1 or 2, inwhich said S(+)-phenyl alkanoic acid is S(+)-ibuprofen and saidα-hydroxyalkanoic acid is in the D-form.
 7. Pharmaceutical preparationcontaining one or more complexes to claim 1 and a physiologicallycompatible extender or carrier.
 8. Pharmaceutical preparation accordingto claim 7 in which said α-hydroxyalkanoic acid is a basicα-hydroxyalkanoic acid.
 9. Pharmaceutical preparation according to claim7 or 8 in which said S(+)-phenyl alkanoic acid is a member selected fromthe group consisting of S(+)-ibuprofen and S(+)-naproxen, and saidcomplex represents an amount by weight of 0.1 to 90% (w/w) of saidpreparation.
 10. A complex according to claim s 7 or 8, characterized inthat the S(+) phenyl alkanoic acid has a structure of the form ##STR4##in which R is lower alkyl, Ar is a member selected from the groupconsisting of monocyclic, polycyclic and ortho-condensed polycyclicaromatic groups having up to twelve carbons in the aromatic system, andsubstituted derivatives of said aromatic groups bearing substituentsselected from the group consisting of halogen atoms, C₁ -C₄ -alkyls,benzyl, hydroxy, C₁ -C₂ alkoxy, phenoxy and benzoyl groups.
 11. Acomplex according to claim 10, in which Ar is a member selected from thegroup consisting of 4-isobutyl-phenyl, 3-phenoxy-phenyl,2-fluoro-4-diphenyl, 4'-fluoro-4-diphenyl, 6-methoxy-2-naphthyl,5-chloro-6-methoxy-2-naphthyl, 5-bromo-6-methoxy-naphthyl,4-chlorophenyl, 4-difluoro-methoxy-phenyl, 6-hydroxy-2-naphthyl and5-bromo-6-hydroxy-2-naphthyl.
 12. A method for the preparation of acomplex of an S(+)-phenyl alkanoic acid and an α-hydroxyalkanoic acid,said method comprising:(a) combining said S(+)-phenyl alkanoic acid withan aqueous buffer solution having a pH range of 5.5 to 7.5 at 20° C.;(b) heating the combined acid and buffer solution of step (a) to 40° C.with constant stirring until a clear transparent solution is obtainedand all of said S(+)-phenyl alkanoic acid is dissolved; (c) adjustingthe pH of the solution resulting from step (b) to 5.5-6.0 by theaddition of diluted phosphoric acid, then adding said α-hydroxyalkanoicacid in an equimolar amount relative to said S(+)-phenyl alkanoic acidto form a reaction mixture; and (d) after complex formation is complete,cooling said reaction mixture to precipitate therefrom said complex incrystalline form, and recovering said precipitated complex from saidreaction mixture.
 13. A method for the preparation of a complex of anS(+)-phenyl alkanoic acid and an α-hydroxyalkanoic acid, said methodcomprising:(a) combining said S(+)-phenyl alkanoic acid with an aqueousbuffer solution having a pH range of 5.5 to 7.5 at 20° C.; (b) heatingthe combined acid and buffer solution of step (a) to 40° C. withconstant stirring until a clear transparent solution is obtained and allof said S(+)-phenyl alkanoic acid is dissolved; (c) adjusting the pH ofthe solution resulting from step (b) to 5.5-6.0 by the addition ofdiluted phosphoric acid, then adding said α-hydroxyalkanoic acid in anequimolar amount relative to said S(+)-phenyl alkanoic acid to form areaction mixture; and (d) after complex formation is complete,evaporating solvent from said reaction mixture to leave an amorphoussolid, and recovering said solid.
 14. A pharmaceutical preparationaccording to claim 7, in which said S(+)-phenyl alkanoic acid is amember selected from the group consisting of S(+)-ibuprofen andS(+)-naproxen, and said pharmaceutical preparation contains from 50 to800 mg of said S(+)-phenyl alkanoic acid.
 15. A pharmaceuticalpreparation according to claim 7, in which said S(+)-phenyl alkanoicacid is a member selected from the group consisting of S(+)-ibuprofenand S(+)-naproxen, and said pharmaceutical preparation contains from 100to 600 mg of said S(+)-phenyl alkanoic acid.
 16. A pharmaceuticalpreparation according to claim 7, in which said S(+)-phenyl alkanoicacid is a member selected from the group consisting of S(+)-ibuprofenand S(+)-naproxen, and said pharmaceutical preparation contains from 100to 300 mg of said S(+)-phenyl alkanoic acid.
 17. A pharmaceuticalpreparation according to claim 7 in the form of an isotropic solution inwhich:(a) said one or more complexes are dissolved in said carrier in aform which is a member selected from the group consisting ofmonomolecular and ionic forms; (b) said one or more complexes is in aconformation which is a member selected from the group consisting ofnative and enantiomeric conformations; (c) the molar fraction of saidone or more complexes relative to said pharmaceutical preparation isfrom 0.001 to 0.67; (d) said carrier is molten, phase-uniform andisotropic at body temperature; (e) said isotropic solution solidifies atroom temperature; (f) said isotropic solution when solidified iscrystalline or noncrystalline, and contains said one or more complexesin crystalline form or in a form which can be crystallized out of saidsolidified isotropic solution; (g) said isotropic solution has anosmotic pressure and effects a molar freezing point reduction; and (h)said one or more complexes has a temperature-dependent diffusioncoefficient and a temperature-dependent specific conductivity.
 18. Amethod for achieving an anti-inflammatory, antipyretic, antimicrobial oranalgesic effect in a subject, said method comprising treating saidsubject with a therapeutically effective amount of a complex accordingto claim
 7. 19. A method in accordance with claim 18 comprising orallyor parentally administering said complex to said subject at a dosage of50 to 1200 mg daily.
 20. A method in accordance with claim 18 comprisingorally or parentally administering said complex to said subject at adosage of 100 to 800 mg daily.
 21. A method in accordance with claim 18in which said S(+)-phenyl alkanoic acid is S(+)-ibuprofen, and saidmethod comprises orally or parentally administering said complex to saidsubject at a dosage of 200 to 600 mg daily.
 22. A method in accordancewith claim 18 comprising topically administering said complex to saidsubject at a dosage of 10 to 200 mg daily.